The Host Genetics of Age-Dependent Susceptibility

年龄依赖性易感性的宿主遗传学

基本信息

批准号：
10007171
负责人：
VINEET D MENACHERY
金额：
$ 24.59万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007171
关键词：
Age Aging Animals Automobile Driving Breathing Candidate Disease Gene Case Fatality Rates Cause of Death Chromosome Mapping Communicable Diseases Coronavirus Infections Data Disease Disease Outbreaks Disease Outcome Elderly Family Foundations Functional disorder Future Genes Genetic Genetic Structures Genetic Variation Goals Health Immune response Immunity Inbred Strains Mice Infection Influenza A virus Link Maps Mediating Mus Outcome Pathogenesis Patients Phenotype Play Population Population Heterogeneity Predisposition Process Quantitative Trait Loci Resistance Respiratory Tract Infections Role SARS coronavirus Severe Acute Respiratory Syndrome Time Treatment outcome Tumor-infiltrating immune cells Variant Viral Load result Virus Virus Diseases age related aged chikungunya genetic element genetic resource genomic locus immune function improved insight mortality mouse genetics mouse model novel older patient phenotypic data population based screening senescence validation studies

项目摘要

Abstract Both aging and host genetics play a critical role in susceptibility to viral infection. In our proposal, we use the Collaborative Cross (CC), a novel mouse genetic resource, to explore how host genetics impacts age dependent susceptibility to infection. Infection with Severe Acute Respiratory Syndrome coronavirus (SARS- CoV), the first outbreak virus of the 21st century, caused a range of respiratory infection with more serve disease observed in patients over the age of 50. Importantly, aging susceptibility is conserved in mouse models of SARS-CoV infection and increased disease is not due to higher viral load in older animals. The results indicate host responses drive differential disease in the aged. However, age-dependent susceptibility is not completely conserved across the genetically diverse CC populations. Screening eleven CC lines with SARS-CoV infection at 18 months old, we identified seven lines with more disease as they aged, three lines equivalent to their younger controls, and one line more resistant as it aged. Together, our preliminary results indicate that certain genetic elements contribute to age-dependent susceptibly to SARS-CoV infection. Building from this screen, we will generate an F2 cross using a CC line with age-dependent susceptibility and a CC line without; we will then challenge both young and aged F2 mice to further characterize genetic loci that contribute to SARS-CoV disease and to identify QTL specifically associated with aging and age-dependent disease. We anticipate that these novel genetic loci will provide a foundation for understanding the role of genetic diversity in SARS-CoV disease and aging processes. We expect the results to also to inform future treatment approaches for elderly patients.

抽象的衰老和宿主遗传学在病毒感染的易感性中发挥着关键作用。在我们的提案中，我们使用 Collaborative Cross (CC)，一种新型小鼠遗传资源，用于探索宿主遗传学如何影响年龄依赖于感染的易感性。严重急性呼吸系统综合症冠状病毒（SARS- 冠状病毒（CoV）是 21 世纪第一个暴发的病毒，引起了一系列呼吸道感染，在 50 岁以上的患者中观察到的疾病。重要的是，小鼠的衰老易感性是保守的 SARS-CoV 感染模型和疾病增加并不是由于老年动物的病毒载量较高。这结果表明，宿主反应会导致老年人罹患不同的疾病。然而，年龄依赖性易感性在遗传多样性的 CC 群体中并不完全保守。筛选 11 个 CC 线 18 个月大时感染 SARS-CoV，我们发现了 7 个品系随着年龄的增长患病率更高，其中 3 个品系相当于他们年轻的对照，并且随着年龄的增长，一根线的抵抗力更强。总之，我们的初步结果表明某些遗传因素导致年龄依赖性的 SARS-CoV 感染易感性。建筑从此屏幕中，我们将使用具有年龄依赖性易感性的 CC 系和 CC 系生成 F2 杂交没有;然后，我们将挑战年轻和年老的 F2 小鼠，以进一步表征有助于 SARS-CoV 疾病并鉴定与衰老和年龄依赖性疾病特异性相关的 QTL。我们预计这些新的遗传位点将为理解遗传多样性的作用提供基础 SARS-CoV 疾病和衰老过程。我们希望结果也能为未来的治疗提供信息针对老年患者的方法。